Antiparasitic dinitroaniline-ether phospholipid hybrids

Design, synthesis, computational studies and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids

DOI: 10.15490/fairdomhub.1.investigation.594.1

Zenodo URL: None

Created at: 4th May 2023 at 16:37

Contents

Computational identification of potential dinitroaniline binding sites in kinetoplastid alpha-tubulin

Sequence and electrostatic potential analyses to identify sites in tubulins that differ between dinitroaniline-sensitive and dinitroaniline-resistant species.

Multiple sequence alignment

Alignments of various alpha-tubulin and beta-tubulin sequences from dinitroaniline-sensitive and dinitroaniline-resistant species. Sequences were retrieved from UniProt with the identifiers listed below and subjected to a multiple sequence alignment using ClustalOmega ([ebi.ac.uk/Tools/msa/clustalo/](https://www.ebi.ac.uk/Tools/msa/clustalo/); ClustalOmega webserver, last accessed 16-02-23):

alpha-tubulin:
- [dinitroaniline sensitive]
T. cruzi - Q27352; T. brucei brucei - Q4GYY5; L. infantum -
...

Multiple sequence alignment of selected alpha-tubulins from dinitroaniline-sensitive and -resistant species

Clustal Omega multiple sequence alignment result for selected alpha-tubulins in FASTA format with gaps. Species and corresponding Uniprot identifiers can be found in the FASTA file.

The following species (Uniprot ID, dinitroaniline-sensitive/resistant) were considered:
- Trypanosoma cruzi (Q27352, sensitive)
- Trypanosoma brucei brucei (Q4GYY5, sensitive)
- Leishmania infantum (E9AGJ8, sensitive)
- Leishmania donovani (I3W8N6, sensitive)
- Leishmania major (Q4QGC5, sensitive)
- Toxoplasma gondii
...

  • alpha-tubulin_msa-clustalomega.fasta

Multiple sequence alignment of selected beta-tubulins from dinitroaniline-sensitive and -resistant species

Clustal Omega multiple sequence alignment result for selected beta-tubulins in FASTA format with gaps. Species and corresponding Uniprot identifiers can be found in the FASTA file.

The following species (Uniprot ID, dinitroaniline-sensitive/resistant) were considered:
- Trypanosoma cruzi (Q8STF3, sensitive)
- Trypanosoma brucei brucei (Q4GYY6, sensitive)
- Leishmania infantum (A4HZJ3, sensitive)
- Leishmania donovani (I3W8N7, sensitive)
- Leishmania major (Q4QBZ6, sensitive)
- Toxoplasma gondii
...

  • beta-tubulin_msa-clustalomega.fasta

Comparative electrostatic analysis of dinitroaniline-sensitive and -resistant tubulins

Creation of homology models of various tubulins from dinitroaniline-sensitive and -resistant species, and a comparative analysis of their electrostatic potential grids overall and in putative binding site regions using PIPSA (Protein Interaction Property Similarity Analysis).

Archive of PIPSA results

This archive contains all results of the PIPSA analysis run in zipped form. It contains the following subfolders:
- apbs: Computed electrostatic potential grids, all log files and similarity matrices for the full protein
and all sites.
- pdb2pqr: PQR files: conversion results after processing uploaded PDB files with pdb2pqr
- pdbs: Original uploaded PDB files

The following sites have been analyzed (provided are site center (based on T. cruzi model, Ca of the residue)
and the sphere radius):

Blume
...

  • pipsa_results_full.zip

Archive of alpha-tubulin homology models

Collected PDB-files of homology models of alpha-tubulin, all based on T. thermophila tubulin PDB-ID 5ubq, chain A:

Includes models of the following dinitroaniline herbicide sensitive species (UniProt ID in brackets):
- C. reinhardtii (P09204)
- E. indica (O22347)
- L. donovani (I3W8N6)
- L. infantum (E9AGJ8)
- L. major (Q4QGC5)
- P. falciparum (P14642)
- S. viridis (Q65C79)
- T. brucei (Q4GYY5)
- T. cruzi (Q27352)
- T. gondii (P10873)
- Z. mays (P14640)

Includes models of the following dinitroaniline
...

  • a-tubulin_homology_models.zip

SOP PIPSA

General SOP for the webPIPSA workflow to study electrostatic potential differences of full alpha-tubulin homology models and various putative binding site regions

  • sop_pipsa.pdf

SOP Homology modeling of alpha-tubulins

General SOP for alpha-tubulin homology model building

  • sop_homology_modeling.pdf

SOP tubulin protein preparation

SOP for protein preparation steps performed for alpha-tubulin homology models (hydrogen addition, hydrogen bonding network optimization and energy minimization)

  • sop_receptor-preparation.pdf

Docking studies of trifluraline and the dinitroaniline-etherphospholipid hybrids against kinetoplastid alpha-tubulin

Induced fit docking studies of the dinitroaniline parent trifluraline and the newly designed dinitroaniline-etherphospholipid hybrids against different potential binding sites in monomeric and multimeric kinetoplastid tubulin receptors.

Preparation of multimeric tubulin docking receptors

Prepared multimeric tubulin protein receptors for docking studies, generated by alignment of two identical models of alpha-tubulin on alpha-tubulin chains of two neighboring protofilaments.

L. donovani alpha-tubulins from neighboring protofilaments

Leishmania donovani multimeric alpha-tubulin protein receptor for docking studies, generated by alignment of two identical models of L. donovani alpha-tubulin on template 5ubq alpha-tubulin chains of two neighboring protofilaments (A, C).

  • ldonovani_alpha-tubulin-protofilament.pdb

L. infantum alpha-tubulins from neighboring protofilaments

Leishmania infantum multimeric alpha-tubulin protein receptor for docking studies, generated by alignment of two identical models of L. infantum alpha-tubulin on template 5ubq alpha-tubulin chains of two neighboring protofilaments (A, C).

  • linfantum_alpha-tubulin-protofilament.pdb

T. brucei alpha-tubulins from neighboring protofilaments

Trypanosoma brucei multimeric alpha-tubulin protein receptor for docking studies, generated by alignment of two identical models of T. brucei alpha-tubulin on template 5ubq alpha-tubulin chains of two neighboring protofilaments (A, C).

  • tbrucei_alpha-tubulin-protofilament.pdb

T. cruzi alpha-tubulins from neighboring protofilaments

Trypanosoma cruzi multimeric alpha-tubulin protein receptor for docking studies, generated by alignment of two identical models of T. cruzi alpha-tubulin on template 5ubq alpha-tubulin chains of two neighboring protofilaments (A, C).

  • tcruzi_alpha-tubulin-protofilament.pdb

Induced-fit docking studies

Docking results of trifluraline and dinitroaniline-etherphospholipid hybrids against different kinetoplastid alpha-tubulin receptors with an induced fit docking routine. The docking protocol involves an initial crude ligand placement step, subsequent receptor optimization in response to ligand binding, and another docking step into the optimized receptor.

L. donovani alpha-tubulin M-loop top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-5 and 7-9, docked to the the M-loop region of a Leishmania donovani alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the M-loop region residue Leu286 (T. cruzi numbering). No result was obtained for compound 6.

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking
...

  • ldonovani-atub_mloop_ifd.zip

L. donovani alpha-tubulin N-loop top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the N-loop region of a Leishmania donovani alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the N-loop region residue Phe49 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
(Schrödinger, LLC, New York, NY, Schrödinger
...

  • ldonovani-atub_nloop_ifd.zip

L. donovani alpha-tubulin MN-loop interface top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the interface region between two neighboring alpha-tubulin monomers of Leishmania donovani;
alpha-tubulin homology models were built on PDB-ID 5ubq and two monomeric models were aligned to neighboring protofilaments of the original PDB-ID 5ubq to construct an interface-model receptor. The docking grid was centered on the M-loop region residue
...

  • ldonovani-atub_mnloop_ifd.zip

L. infantum alpha-tubulin M-loop top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the M-loop region of a Leishmania infantum alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the M-loop region residue Leu286 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
(Schrödinger, LLC, New York, NY, Schrödinger
...

  • linfantum-atub_mloop_ifd.zip

L. infantum alpha-tubulin N-loop top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the N-loop region of a Leishmania infantum alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the N-loop region residue Phe49 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
(Schrödinger, LLC, New York, NY, Schrödinger
...

  • linfantum-atub_nloop_ifd.zip

L. infantum alpha-tubulin MN-loop interface top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-5 and 7-9, docked to the interface region between two neighboring alpha-tubulin monomers of Leishmania infantum; alpha-tubulin homology models were built on PDB-ID 5ubq and two monomeric models were aligned to neighboring protofilaments of the original PDB-ID 5ubq to construct an interface-model receptor. The docking grid was centered on the M-loop region
...

  • linfantum-atub_mnloop_ifd.zip

T. brucei alpha-tubulin M-loop top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the M-loop region of a Trypanosoma brucei alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the M-loop region residue Leu286 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
(Schrödinger, LLC, New York, NY, Schrödinger
...

  • tbrucei-atub_mloop_ifd.zip

T. brucei alpha-tubulin N-loop top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the N-loop region of a Trypanosoma brucei alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the N-loop region residue Phe49 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
(Schrödinger, LLC, New York, NY, Schrödinger
...

  • tbrucei-atub_nloop_ifd.zip

T. brucei alpha-tubulin MN-loop interface top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-5 and 7-9, docked to the interface region between two neighboring alpha-tubulin monomers of Trypanosoma brucei; alpha-tubulin homology models were built on PDB-ID 5ubq and two monomeric models were aligned to neighboring protofilamentsof the original PDB-ID 5ubq to construct an interface-model receptor. The docking grid was centered on the M-loop region residue
...

  • tbrucei-atub_mnloop_ifd.zip

T. cruzi alpha-tubulin M-loop top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, and reference compound trifluraline, docked to the M-loop region of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the M-loop region residue Leu286 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
...

  • tcruzi-atub_mloop_ifd.zip

T. cruzi alpha-tubulin N-loop top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, and reference compound trifluralin, docked to the N-loop region of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the N-loop region residue Phe49 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
...

  • tcruzi-atub_nloop_ifd.zip

T. cruzi alpha-tubulin MN-loop interface top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-5 and 7-9, docked to the interface region between two neighboring alpha-tubulin monomers of Trypanosoma cruzi; alpha-tubulin homology models were built on PDB-ID 5ubq and two monomeric models were aligned to neighboring protofilaments of the original PDB-ID 5ubq to construct an interface-model receptor. The docking grid was centered on the M-loop region residue
...

  • tcruzi-atub_mnloop_ifd.zip

T. cruzi alpha-tubulin Blume site top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for dinitroaniline etherphospholipid hybrid compounds 1, 2, 4, 5 and 9 and reference compound trifluraline, docked to the Blume site of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on site residue Ala4 (T. cruzi numbering). No results were obtained with compounds 3 and 6-8.

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the
...

  • tcruzi-atub_blume_ifd.zip

T. cruzi alpha-tubulin Consensus site top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1, 4, 8 and reference compound trifluraline, docked to the Consensus site (Delye, Mitra & Sept) of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on site residue Thr239 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
...

T. cruzi alpha-tubulin Consensus site top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1, 4, 8 and reference compound trifluraline, docked to the Consensus site (Delye, Mitra & Sept) of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on site residue Thr239 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
...

  • tcruzi-atub_consensus_ifd.zip

T. cruzi alpha-tubulin pironetin site top complexes from induced fit docking

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1, 2, 4, 8 and reference compound trifluraline, docked to the pironetin site of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on site residue Leu238 (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced Fit docking workflow
(Schrödinger, LLC,
...

  • tcruzi-atub_pironetin_ifd.zip

T. cruzi alpha-tubulin top complexes from induced fit docking based on trifluraline reference in Blume site

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1-2, 4-5 and 7-8, docked to the resulting complex of reference compound trifluralin in the Blume site of a
Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin
reference compound (T. cruzi numbering). No results were obtained for compounds 3, 6 and 9.

The docking results were obtained by Induced Fit docking
...

  • tcruzi-atub_trifluralin-blume_ifd.zip

T. cruzi alpha-tubulin top complexes from induced fit docking based on trifluraline reference in Consensus site

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compounds 1-5 and 7-8, docked to the resulting complex of reference compound trifluralin in the Consensus site of a
Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin
reference compound (T. cruzi numbering). No results were obtained for compounds 6 and 9.

The docking results were obtained by Induced Fit docking
...

  • tcruzi-atub_trifluralin-consensus_ifd.zip

T. cruzi alpha-tubulin top complexes from induced fit docking based on trifluraline reference in M-loop region

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the resulting complex of reference compound trifluralin to the M-loop region of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin
reference compound (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced
...

  • tcruzi-atub_trifluralin-mloop_ifd.zip

T. cruzi alpha-tubulin top complexes from induced fit docking based on trifluraline reference in N-loop region

Zip-archive with top-ranked (by IFDScore) induced fit docking results for each dinitroaniline etherphospholipid hybrid compound, compound 1-9, docked to the resulting complex of reference compound trifluralin to the N-loop region of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin reference compound (T. cruzi numbering).

The docking results were obtained by Induced Fit docking with Schrödinger Glide and Prime in the Induced
...

  • tcruzi-atub_trifluralin-nloop_ifd.zip

T. cruzi alpha-tubulin top complexes from induced fit docking based on trifluraline reference in pironetin site

Zip-archive with top-ranked (by IFDScore) induced fit docking results for dinitroaniline etherphospholipid hybrid compounds 1-4 and 7-8 docked to the resulting complex of reference compound trifluralin in the pironetin site of a Trypanosoma cruzi alpha-tubulin homology model built on PDB-ID 5ubq. The docking grid was centered on the trifluralin reference compound (T. cruzi numbering). No results were obtained for compounds 5, 6 and 9.

The docking results were obtained by Induced Fit docking with
...

  • tcruzi-atub_trifluralin-pironetin_ifd.zip

SOP Induced fit docking

SOP describing application of the Induced fit docking workflow to Trypanosoma and Leishmania alpha-tubulin receptors.

  • sop_ifdocking.pdf
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Citation
Poehner, I., Wade, R., & Cordeiro-Da-Silva, A. (2023). Antiparasitic dinitroaniline-ether phospholipid hybrids. FAIRDOMHub. https://doi.org/10.15490/FAIRDOMHUB.1.INVESTIGATION.594.1
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Created: 4th May 2023 at 16:37

Last updated: 4th May 2023 at 16:38

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